TWI237637B - 5-trityloxymethyl-oxazolidinones and process for the preparation thereof - Google Patents

Abstract

A method for preparing protected, preferably chiral, 5-trityloxymethyl-oxazolidinone in one step directly from optically active 3-hydroxy-4-trityloxy butyramide is described. Oxazolidinones are an important class of molecules in the pharmaceutical industry especially in the areas of antimicrobials and behavioral disorders.

Description

1237637 A7 V. Description of the invention (01 Name: 5_Dibenzomethylmethyl 4-money_ and its preparation method Abstract:-Description of the invention-Kind of single-Bucai direct spin optical properties of 3 times Jidong Dibenjia Method for the preparation of protected but preferably palmitic S-tribenzyl methacetate by oxybutyramine. The sigma-stomach σ is an important molecule in the pharmaceutical industry, especially in antimicrobials Agents and Behavioral Disorders Details: < MM Related Applicant Zhu 1 Tomb of Wuzhan --- 0 ^-(Please read the precautions on the back before filling out this page) Staff Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed without background of invention (Invention collar) The present invention relates to a single-stage path for preparing 5-dibenzyloxymethyloxazolidinone from 3-sil · 4 · triphenyl ^ butoxymidine. This invention It is particularly relevant to the preparation of the palmitate form of 5-tribenzyloxymethyloxazolidinone. (2) iKMMMAJL The oxazolidinone with optical purity can be obtained by using reagents such as phosgene, ethyl chloroformate and carbonylimidazole It is prepared by carbonylating a vicinal amine alcohol. Preparation of 5. · tribenzyloxymethyl oxazolidone with optical purity In general, it is necessary to prepare the corresponding 5-transmethyl humidone with optical purity, and then perform a tritylation step to obtain 5-tribenzyloxymethyl sigmazodone. ° 哫 峻 哫Ketones are obviously a very important class of compounds in drug development, especially in the field of antimicrobial agents (〇4] ^ 11 ^ ， 〇. 了. Et al., 〇1'1 ^ 59 This paper standard applies to Chinese national standards ( CNS) A4 specification (210X297 mm) Order 4. 1237637 A7 B7 V. Description of the invention (02) (Please read the notes on the back before filling this page) 7-16 (2000)) and behavioral disorders (Brenner, R, etc. Human, cnn Ding Yi ^ such as 22 4 411-419 (20_. Especially has activity against some of the most resistant human pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, anti-cephalosporin Streptococcus pneumoniae and several organisms that show resistance to cyanogenin (Diekema 'D. J. et al., J) rugs 59 7-16 (2000)). LineZoid (4) is a recent recommendation Drugs used to treat infections with antibiotic-resistant strains, especially those resistant to vancomycin.

Optically active 3,4-dihydroxybutyric acid and its r-lactone are important sources of palmity. It can be obtained from sugars such as starch, lactose, maltodextrin, cellulose and arabinose by oxidative degradation in industrial quantities (Hollingsworth, RI Biotechnology Annual Review 2 281-291 (1996); employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives

Hollingsworth, R.I., J. Org. Chem. 64 7633-7634 (1999)). See also U.S. Patent Nos. 5,292,939, 5,080,107, 5,319,110, and 5,374,773 of Hollingsworth. Palmitic aminopropanediol can be prepared by Hoffman degradation of isopropylidene acetal of optically active 3,4-dihydroxybutyric acid amine (Wang, G. et al., J Org. Chem. 64 1036-1038 (1999)). SUMMARY OF THE INVENTION The present invention relates to a method for preparing 5-tribenzyloxymethyloxazolidone, which includes: 5 paper sizes applicable to Chinese National Standard (CNS) A4 (210 X 297 mm)! 237637 Μ Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards V. Description of the Invention (〇3) (a) In the presence of metal or alkaline earth metal hydroxides and organic solvents, it is known that 3,4-dichlorobutanol in the reaction milk compound 4-tritylamine of amine and metal or earth metal hyporhenate are stirred in water for reaction to obtain 5-trityloxymethyl 4 π sitting bite ketone; (b) from organic solvents The reaction mixture in was isolated from the 5-trityloxymethyl group. Nozolidinone; and (c) removing the hydrazone organic solvent to obtain the 5-tribenzylmethoxine pyridine pyridine. The invention also relates to a novel 5-trityloxymethyl group made by this method. No. azolidinone 1. The compound is preferably palmar. OBJECTS OF THE INVENTION Therefore, the object of the present invention is to propose a single-stage method for producing novel 4 5 · trityloxymethyl ketones from a trityl group that can be brewed from amines. In addition, one object of the present invention is to propose the preparation of palm products. In addition, the purpose of the present invention is to propose a simpler and more economical method than the previous technique to produce the product at a high rate and purity. Refer to the following y, +, ° > descriptions below to make this other purpose more clear. The description of the preferred embodiment is as follows: The reaction involved in the method of the present invention is shown in Figure 1 below. Η 一 ΟΗ 〇 2 ΟΟΓ / ΟΗΓ •-νη2

Scheme 6 This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm ------ 哝 ------ 1T ----- d (Please read the precautions on the back before filling this page )

I Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

The size of this paper is suitable (210x297 mm) 1237637 V. Description of the invention (05) The amine test is better to read out. Only other amines such as triethylamine can be used to produce HCI or other acids produced in this reaction. Perform the reaction. The organic solvent is preferably a mixture of dimethylformamide and tetrahydrofuran, and does not contain water. The solvent is preferably removed, and then washed with diethyl ether to remove i 4 dimethyl T-based hydrazone. This temperature is between about 5. & 4Q < t, and the pressure is atmospheric. The reaction was completed in 24 to 48 hours. This triglycinic acid is subsequently used to form the mouthpiece g. Therefore, the present invention proposes a triphenylmethyl-protected, 5-methyl group + seat bite with a degree such as ⑻_5-tritylmethoxymethyl 4 酉 酉 with ⑴ ', which is in a simple and high yield method 'Using palmarity 3, the cardinal dimer radical I, "4-0-trityl-" as the starting material, and spin optically sulfonyl-r-butyrolactone. ^ Isocyanate hydrolyzed by water is Huffman (secret = medium (intermediate substance 'basically connected via a radical can be used as a cyclization to form a ketone system. In the present invention, the use of phosgene, =:?: Divided into individual carbonylation reactions. This is said that butyric acid _ (like 4: = acid succinic acid-including open %% sequence basically consists of only two steps, of which only one has ## 1. 第 — Steps are based on the treatment of 2-butyridine S! Amine 2 --- ammonia solution in aqueous 3-Λdidiyl. This donkey amine is used at room temperature to quantify I 1T (please first Read the notes on the back and fill in this f) 1237637 A7 V. Invention description (06 Intermediate isocyanate is protected to isolate water, so that adjacent groups participate in 'while protecting the final product to prevent hydrolysis. Use 2-Phase Solvent System _-In this case, Tetrahydrocondensate / water-the Huffman rearrangement directly produces a few fidelity methyl succinates, with an isolated yield of> 90%, and Optical purity> 9 and 9 percentages. This condition indicates that in 4 basic steps, the synthesis from the powder, maltose, «or similar 4_ bond sugar source is important, bright Purity, 5--like 5- (methyl ether phase is very important economical. The trityl group can be selectively removed, so that the H methyl functionality is transformed into a variety of substituents. The ring nitrogen It can also be replaced by hydrogen to be fluorinated or donated. The two characteristics make it easy to obtain a possible drug candidate with great potential. The example / underline is to prepare a protected 5-triphenylmethoxymethyl group. Oxidazolidone Preparation by the Central Associate of the Ministry of Economic Affairs, Cooperative Society, Preparation of 3-Hydroxytriphenoxybutyridamine, ”" Mkol ", (S) -3,4-Dimethyl-butyric acid amine Dissolved in 50 ml of tetrahydrofuran and% == dimethylformamide, add 1G ml_ group, and then · g (0 mol) of trityl chloride in the flask. Use filled with chlorine Dry the tube of calcium to remove moisture. The reaction mixture was stirred off at room temperature for 36 hours. After this period of time, it was filtered to remove solids. The liquid was concentrated under reduced pressure to remove large solvents. The solution was poured into ice water and stirred for half an hour, and the aqueous layer was removed from the stilbamine protected by Sanben #. The obtained semi-crystalline liquid product was dried on a base. Wet mill to wash away excess trityl chloride. Yield: 33.0 g (91%). Physical data: melting point 59 | 600 (it is === dichloromethane: hexane: acetone = 6: 3: 〇 · 5) [α] 'Mb. (Two copies of this paper ruler Guan Jiaxian (c is called public y 1237637 A7 B7 V. Description of the invention (08) (Mosher's acid)) GC analysis of the derivative, the product Optical purity> 99.9 ei Those who are familiar with this technique can deprotect the 5-triphenoxymethyl-pyrazolidone (such as hydrogenolysis or HBr treatment) according to customary methods, and use it to prepare important 5- Acetaminophenmethylpyrazolidone (as described in various patents, such as US Patent No. 5,837,870 to Pearlman et al.). The hydroxyl group can be converted into a nitrogen-containing functional group by any known method. These methods include mesylation or tosylation, followed by substitution with ammonia, azide, benzylamine, and other nitrogen nucleophiles, as shown in Scheme 2 below. People .MesylcWoride 9 '' Ten ^ R Pyridke- 1 R 1 ίί " or-H2

〇A

R I ------ I- 丨 ~ # -I (Please read the notes on the back before filling this page)

MsO

〇 NT HO,

Ο N ‘TrO

0) N3. (B) H2 / catalyst (c) Ac20

00A 〇 NH

* · * 聿 RX plu ^ catalyst (X = halogen) H0 〇H

, 1T

〇 N AcHN

ΟΕΓ _ · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

OK HO NH2

Fork 〇 NH HO

HO NH2 HO

Scheme 2

TrO. The foregoing description is only used to illustrate the present invention, and the present invention is limited only by the scope of the following patent applications. 11 This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

Claims (1)

237637 No. 090122961 No. 090122961, May 18, 1994 Replacement of the revised version (01) Application for patent scope 'A method for preparing 5-tribenzyloxymethyl-oxazolidinone, which includes: (a) testing metal or In the presence of an alkaline earth metal hydroxide and an organic solvent, the 'trityl ether of 3,4-dihydroxybutanamine in the reaction mixture and an alkali metal or alkaline earth metal hypochlorite are stirred in water for reaction, and (B) isolating trityloxymethylpyrazolone; (b) separating the trityloxymethylpyridoxone from the organic / cereal reaction mixture; and (c) removing the organic solvent to This tribenzomethoxymethyloxazolidone was obtained. -2 3 5 6 If the scope of patent application is the highest! The method of clause, wherein the metal or soil metal hydroxide is sodium hydroxide. Such as the scope of patent application! Or the method of item 2, wherein the organic solvent is separated from water in step (b) by layer separation. ^ The method of claim 1 in which the organic solvent is removed by evaporation. Such as the scope of patent application! The method according to the item, wherein after step =, = 5-trityl_methyl ## _ is purified by dissolving in the presence of a desiccant; methane, and then removing the dichloromethane. Second ^ the scope of patent application! Item method, wherein step 3 in step IX = 4-trityl ether of butylamidine is obtained by using an excess of trityl 3'4_di # 1 butylbutyl_ in organic The reaction is carried out in the presence of a base to produce 4-trityl ether, which is washed away with water to remove excess tritylwei. Divide first and take gluten extract 12 (02) (02) The method according to item 1 of the patent application range, in which methyl 10K is optically pure. Stupid Methoxylate The method of item 1, in which the organic solvent is organic solvent, the sodium salt is! 237637 Tetrahydrooctane 9, and κ The method of item 1 in the scope of patent application, which has-bad mouth conditions. 10. For the method in the first scope of patent application, in which hypochlorite is used. 11. The method of claim 1 in the scope of patent application, wherein this time is hypobromite. 12. The method according to item 1 of the scope of patent application, wherein this is a water-insoluble alcohol. Dioxomethoxymethyl-σ No. Tudou. Halate based organic solvents 13